Determinants of Restoration of CD4 and CD8 Cell Counts and Their Ratio in HIV-1-Positive Individuals With Sustained Virological Suppression on Antiretroviral Therapy.

BACKGROUND: An increasing number of HIV-positive individuals now start antiretroviral therapy (ART) with high CD4 cell counts. We investigated whether this makes restoration of CD4 and CD8 cell counts and the CD4:CD8 ratio during virologically suppressive ART to median levels seen in HIV-uninfected individuals more likely and whether restoration depends on gender, age, and other individual characteristics. METHODS: We determined median and quartile reference values for CD4 and CD8 cell counts and their ratio using cross-sectional data from 2309 HIV-negative individuals. We used longitudinal measurements of 60,997 HIV-positive individuals from the Antiretroviral Therapy Cohort Collaboration in linear mixed-effects models. RESULTS: When baseline CD4 cell counts were higher, higher long-term CD4 cell counts and CD4:CD8 ratios were reached. Highest long-term CD4 cell counts were observed in middle-aged individuals. During the first 2 years, median CD8 cell counts converged toward median reference values. However, changes were small thereafter and long-term CD8 cell count levels were higher than median reference values. Median 8-year CD8 cell counts were higher when ART was started with <250 CD4 cells/mm. Median CD4:CD8 trajectories did not reach median reference values, even when ART was started at 500 cells/mm. DISCUSSION: Starting ART with a CD4 cell count of ≥500 cells/mm makes reaching median reference CD4 cell counts more likely. However, median CD4:CD8 ratio trajectories remained below the median levels of HIV-negative individuals because of persisting high CD8 cell counts. To what extent these subnormal immunological responses affect specific clinical endpoints requires further investigation.

Brief Report: Drop in CD4+ Counts Below 200 Cells/µL After Reaching (or Starting From) Values Higher than 350 Cells/µL in HIV-Infected Patients With Virological Suppression.

BACKGROUND: The aim of the study was to quantify the risk of a drop in CD4 counts below 200 cells/µL after reaching values >350 cells/µL on antiretroviral therapy (ART) (or after starting ART with CD4 count >350 cells/µL) in the absence of virological failure. SETTING: Ambulatory care services, Italy. METHODS: Prospective cohort study of patients enrolled in the ICONA Foundation Study cohort who started ART with >350 CD4/µL or with ≤350 CD4/µL and reached values >350 cells/µL after virological suppression (VS, defined by 2 consecutive viral loads ≤50 copies/mL). The date of CD4 count >350 was the baseline for the analysis and those with ≥1 viral load and CD4 count after baseline were included. The primary end point was the cumulative risk (estimated using the Kaplan-Meier method) of a CD4 drop below 200 cells/µL over follow-up, which was censored at the date of virological failure (confirmed HIV-RNA >50 copies/mL), death, or last visit. RESULTS: Six thousand six hundred sixty-three patients were included. A confirmed CD4 drop below 200 cells/µL was never observed over a median follow-up of 45 (Q1: 21, Q3: 89) months, as long as VS was maintained. Upper limits of the 97.5% confidence interval of rates of confirmed CD4 drop below 200 cells/µL were 0.28 and 0.38/1000 person-years of follow-up for patients with ≤350 and >350 CD4 cells/µL at starting ART. CONCLUSIONS: In patients who started ART in Italy with >350 CD4 cells/µL or reached >350 CD4 cells/µL after VS, the risk of a CD4 drop below 200 cells/µL in those maintaining VS was negligible.

Active HCV Replication but Not HCV or CMV Seropositive Status Is Associated With Incident and Prevalent Type 2 Diabetes in Persons Living With HIV.

OBJECTIVE: To analyze the association between chronic hepatitis C virus (HCV) and cytomegalovirus (CMV) infections with type 2 diabetes in HIV-infected patients. METHODS: HIV-1-infected patients enrolled in ICONA, a prospective cohort study involving 42 tertiary care centers in Italy, were selected with the following characteristics: for the diabetes incidence analysis, all patients with available CMV IgG results (first available test = baseline) and without type 2 diabetes were followed until onset of type 2 diabetes, last available clinical follow-up, death or September 30, 2014, whichever occurred first; for the prevalence analysis, all ICONA patients were analyzed at their last follow-up visit. Main outcome measures were the new onset of type 2 diabetes (incidence analysis) and the prevalence of type 2 diabetes at last follow-up. RESULTS: During 38,062 person-years of follow-up (PYFU) in 6505 individuals, we observed 140 cases of incident type 2 diabetes (Incidence rate 3.7, 95% CI: 3.1 to 4.3, per 1000 PYFU). In a multivariable Poisson regression model, HCV-antibody (Ab)+/HCV RNA+ patients [adjusted relative rate versus HCV-Ab negative 1.73 (95% CI: 1.08 to 2.78)] but not HCV Ab+RNA- or CMV IgG+ patients, had a higher risk of diabetes. Among 12,001 patients, 306 (2.5%) prevalent cases of type 2 diabetes were detected. HCV Ab+RNA+ status was independently associated with prevalent diabetes (adjusted Odds Ratio vs HCV Ab- 2.49; 95% CI: 1.08 to 5.74), whereas HCV-Ab+/HCV RNA- and CMV IgG+ status were not. CONCLUSION: In HIV-infected individuals, active HCV replication but not prior HCV exposure or latent CMV infection is associated with incident and prevalent type 2 diabetes.

Changes in Cognitive Function Over 96 Weeks in Naive Patients Randomized to Darunavir-Ritonavir Plus Either Raltegravir or Tenofovir-Emtricitabine: A Substudy of the NEAT001/ANRS143 Trial.

BACKGROUND: Improvements in cognitive function are described after initiation of combination antiretroviral therapy (cART), with sparse data on differences between cART strategies. METHODS: We assessed changes in cognition, over 96 weeks, in therapy-naive HIV-positive adults randomized to darunavir/ritonavir (800/100 mg once daily) with either raltegravir (400 mg twice daily, Arm1) or tenofovir/emtricitabine (245/200 mg once daily, Arm2). Seven cognitive tests were administered at baseline and week (W) 96. Changes from baseline in individual cognitive test scores and composite score (NPZ) were assessed. Comparisons between treatment arms were by intention to treat and associations with immunological and virological parameters by regression models. FINDINGS: Of 343 subjects enrolled, 208 completed the W96 cognitive assessment. Baseline median (interquartile range) CD4 count and plasma HIV RNA were 348 (282-398) cells per microliter and 4.7 (4.2-5.1) log10 copies per milliliter, respectively. At W96, numbers with plasma HIV RNA undetectable and remaining on randomized cART were 85 (92%) and 110 (96%), and 84 (90%) and 107 (93%) in Arm1 and Arm2, respectively. Overall performance significantly improved by W96 in 5 of 7 individual tests and in NPZ. Mean changes in NPZ were 0.28 versus 0.21 for Arm1 and 2, respectively (P = 0.37). No statistically significant differences between study treatment arms were observed in individual cognitive domains apart from attention (greater improvement in Arm1, P = 0.0499). At W96, NPZ score increase was associated with increase in CD4 (P = 0.001) but not HIV RNA area under curve (P = 0.60). INTERPRETATION: Subsequent to the initiation of cART, immunological recovery rather than type of antiretroviral therapy is the major driver of changes in cognitive function.

Brief Report: Soluble CD163 in CMV-Infected and CMV-Uninfected Subjects on Virologically Suppressive Antiretroviral Therapy in the ICONA Cohort.

AIMS: To contribute to the understanding of the role played by cytomegalovirus (CMV) in sustaining monocyte/macrophage-mediated immune activation in antiretroviral therapy treated HIV-infected subjects. DESIGN AND METHODS: We selected 23 CMV-uninfected and 46 CMV-infected HIV+ subjects, matched for age, CD4 nadir, HIV infection duration, and viral hepatitis serostatus. All subjects were on successful antiretroviral therapy since at least 1 year. A group of 16 healthy donors with similar age and sex was also included. Plasma levels of tumor necrosis factor-alpha, interleukin-6, sCD163, sCD14, and CMV immunoglobulin G levels were measured in duplicate with human enzyme-linked immunosorbent assay kits. RESULTS: We found significantly higher sCD163 plasma levels in HIV+CMV+ compared with HIV+CMV- subjects and healthy donors. This augmentation was confirmed also when subjects positive for hepatitis C virus-Ab were excluded from analysis. Interestingly, a correlation between anti-CMV immunoglobulin G levels and sCD163, tumor necrosis factor-alpha, interleukin-6, and sCD14 in HIV+CMV+ subjects was found. CONCLUSIONS: CMV coinfection could be a major driver of monocyte/macrophage activation in virally suppressed HIV+ individuals and might explain the increased risk of non-AIDS morbidity/mortality in HIV/CMV-coinfected subjects.

Discontinuation of Initial Antiretroviral Therapy in Clinical Practice: Moving Toward Individualized Therapy.

BACKGROUND: Study aim was to estimate the rate and identify predictors of discontinuation of first combination antiretroviral therapy (cART) in recent years. METHODS: Patients who initiated first cART between January 2008 and October 2014 were included. Discontinuation was defined as stop of at least 1 drug of the regimen, regardless of the reason. All causes of discontinuation were evaluated and 3 main endpoints were considered: toxicity, intolerance, and simplification. Predictors of discontinuation were examined separately for all 3 endpoints. Kaplan-Meier analysis was used for the outcome discontinuation of ≥ 1 drug regardless of the reason. Cox regression analysis was used to identify factors associated with treatment discontinuation because of the 3 reasons considered. RESULTS: A total of 4052 patients were included. Main reason for stopping at least 1 drug were simplification (29%), intolerance (21%), toxicity (19%), other causes (18%), failure (8%), planned discontinuation (4%), and nonadherence (2%). In a multivariable Cox model, predictors of discontinuation for simplification were heterosexual transmission (P = 0.007), being immigrant (P = 0.017), higher nadir lymphocyte T CD4 cell (P = 0.011), and higher lymphocyte T CD8 cell count (P = 0.025); for discontinuation due to intolerance: the use of statins (P = 0.029), higher blood glucose levels (P = 0.050). About toxicity: higher blood glucose levels (P = 0.010) and the use of zidovudine/lamivudine as backbone (P = 0.044). CONCLUSIONS: In the late cART era, the main reason for stopping the initial regimen is simplification. This scenario reflects the changes in recommendations aimed to enhance adherence and quality of life, and minimize drug toxicity.

Life expectancy in the immune recovery era: the evolving scenario of the HIV epidemic in northern Italy.

INTRODUCTION: National cohort and intercohort studies have been set to describe the differences of life expectancy (LE) of HIV-infected individuals. OBJECTIVE: The aim of this study was to assess the impact of immune recovery (IR) on LE of patients with HIV undergoing combination antiretroviral therapy. METHODS: In this retrospective observational study, outcome measure was LE of patients with HIV compared with LE of northern Italian population. Group categorizations were as follows: patients with no immune recovery (nIR), patients with IR, patients who are immune maintained, and pre-highly active antiretroviral therapy (HAART) and post-HAART. Abridged life tables were constructed from age-specific mortality rates (per 1000 person years) to estimate LE from the age of 20-55 years. RESULTS: A total of 9671 patients, 71% men, were included. After 2005, we assisted to a rapid increase in the overall rate of patients attaining IR in the community coupled with a progressive decrease of AIDS death, but not of non-AIDS deaths. In a 40-year-old patient, LE was 38.10 years [standard error (SE) = 2.60], 30.08 years (SE = 0.98), and 22.9 (SE = 0.69) in the IR, post-HAART group and nIR, respectively, compared with 41.38 years of the general Italian population. An approximately 5-year gap in LE was observed in IR patients. DISCUSSION: We describe IR at a "community" level, related to calendar year and apparent 10 years after HAART introduction. HAART community IR is significantly influencing LE and is associated with the changing clinical picture of HIV disease. An increasing gradient of LE exists between nIR, post-HAART, and IR groups, with the latter, above the age of 40 years only, reaching LE of general population.

Incidence, timing, and determinants of bacterial pneumonia among HIV-infected patients: data from the ICONA Foundation Cohort.

BACKGROUND: The aim of the study was to evaluate incidence and determinants of bacterial pneumonia (BP) after starting combination antiretroviral therapy (cART) in the Italian Cohort of Antiretroviral-Naive Patients. METHODS: Patients free from BP at cART initiation enrolled between 1996 and 2011 were analyzed. Kaplan-Meier curves were calculated to estimate the time to the first episode of BP; uni- and multivariable Cox proportional hazard models, with time-updated covariates, were applied to identify the risk factors of the first episode of BP. RESULTS: Four thousand nine hundred forty-two patients were followed for a median of 63.7 months (interquartile range: 23.6, 106.7); 73% were men, median age 36 years (interquartile range: 32, 42), 35% hepatitis C virus antibody positive, 28% smokers, 15% with an AIDS diagnosis (not BP) before cART, 46% with nadir CD4⁺ T-cell count ≤200 cells per microliter. During 27,569 person years, 137 patients developed 156 BPs, for a crude incidence of 5.66 [95% confidence interval (CI): 4.81 to 6.62] per 1000 person years. The probabilities of first BP at 3, 5, 10, and 14 years from cART initiation were 2.0% ± 0.22%, 2.9% ± 0.28%, 4.3% ± 0.42%, and 5.7% ± 0.75%, respectively. The occurrence of a first BP was associated with low nadir CD4⁺ [hazard ratios (HR) (per 100 cells/µL higher) = 0.86, 95% CI: 0.79 to 0.94], low current CD4 [HR (per 100 cells/µL higher) = 0.88, 95% CI: 0.84 to 0.92], high CD8⁺ [HR (per 100 cells/µL higher) = 1.02, 95% CI: 1.01 to 1.03], low hemoglobin [HR (per g/dL higher) = 0.74, 95% CI: 0.71 to 0.78], and unfavorable virological outcome [HR (HIV-RNA >50 vs <50 copies/mL) = 1.29, 95% CI: 1.04 to 1.60] in addition to older age, male gender, non-Italian nationality, smoking, and longer time to cART initiation. CONCLUSIONS: BP is an infrequent clinical event in the cART era and is associated with traditional risk factors, viroimmunological failure to cART, and low hemoglobin.